Psychiatric diagnoses are complex and heterogeneous constructs. Rather than natural kinds, they describe clusters of frequently co-occurring symptoms, which often lack a distinct border between health and disease. This makes it difficult to establish if a dysregulation within a particular brain system contributes to the intial occurrence of an illness, or emerges as a result of pathophysiological processes following onset. Here we propose parsing the heterogeneity of anxiety and affective disorders through the identification of neural and genetic pathways associated with illness risk, onset, and maintenance. With a focus on amygdala-medial prefrontal cortex (mPFC) circuitry, this project will: (1) Establish relations between dimensional measures of affective and social functioning and amygdala-mPFC circuit integrity in psychiatrically healthy treatment naive young adults; (2) Identify associations between previously validated polygenic risk factors for affective illnesses, derived through large-scale case-control GWAS analyses, and amygdala-mPFC circuit integrity; and (3) Establish novel polygenic scores that co-vary with the anatomical and intrinsic integrity of amygdala-mPFC circuitry in healthy young adults, assessing the relations between these scores and the presence of psychiatric illness in an independent case-control dataset. The genetic and biological architecture of the major psychiatric disorders remains largely unknown. The proposed research may enable the identification of new genetic variants, anatomical features, or patterns of brain activity that are characteristic of certain disorders. The identification of novel biological pathways, even ones that contribute a small increment of risk, can suggest new etiological hypotheses and possible treatment targets. Dr. Avram Holmes' primary career goal is to study biological pathways contributing to individual differences in psychiatric illness risk. The proposed project will allow Dr. Holmes to receive training in genetics, advanced imaging methods, and systems neuroscience. In doing so he will develop a translational inter-disciplinary research program that combines molecular genetic and neuroimaging methods. The project will be conducted in the Department of Psychiatry at Massachusetts General Hospital. The specific research sites include the Athinoula A. Martinos Center for Biomedical Imaging and the Center for Human Genetic Research. The associated facilities, resources and environment provide the equipment, space and expertise required for the execution of this research. The proposed project, associated training, and mentorship will form the foundation of Dr. Holmes' independent research program, which will have anxiety and affective disorders as a core clinical focus.